This invention relates to the preparation of formulations comprised of an intimate mixture of active ingredients and excipients. More particularly, the present invention relates to the preparation of such formulations without the use of toxic solvents.
In many commercial fields the final product offered to the consumer or to a processor contains the desired chemical ingredient (often called the active ingredient) diluted in solvents along with other excipients whose presence is required in order to yield the desired chemical or physical performance. This combination of active ingredients plus excipients has been created in order to permit the accurate delivery of the chemical, to enhance the activity of the active ingredient, or to put the active ingredient into a physical form which renders it useful to the customer. Examples of such finished goods are agricultural chemicals, pharmaceuticals, veterinary products, paints, dyes, aerosol sprays, polishes and the like.
When the active ingredient per se is too concentrated, insoluble, or difficult to handle by the consumer it is normally converted into some physical form which renders it useful to the consumer. The conversion may be effected for the commercial purchaser or the active ingredient may be delivered to a third party as an intermediate for additional processing. Thus, the consumer may be a commercial purchaser of the product or someone who purchases the item as the result of another process designed to produce either an end use product or another intermediate. It cannot be deemed that a significant amount of time and effort is spent converting active ingredients into useful physical forms by combining them with excipients. In all of these prior art conversion processes, the goal is to either maintain or enhance the economic usefulness of the active ingredient.
An example of such a prior art conversion process in the agricultural industry is the formulation of Atrazine. Atrazine is a water insoluble, solvent in soluble compound which, when applied to crops at the rate of 1 lb. of active ingredient per acre, controls a variety of economically harmful grasses. As synthesized, the product is a solid material that will not readily disperse in water (the carrier system typically used by farmers to apply crop chemicals). However, after mixing the active ingredient with suitable excipients, the resulting commercial formulation that is made available to the farmer readily disperses in water. In this form the active ingredient is of economic value to the grower. The value and need to prepare such formulations is equally evident in other areas of chemistry such as pharmaceuticals and veterinary products.
Heretofore, the process by which active ingredients are mixed with the necessary excipients have involved the use of volatile solvents, such as aromatic or aliphatic hydrocarbons, ketones, alcohols, etc. The public, however, is presently growing more concerned with the environment. Among the many concerns are the effects that the emission of solvents has on the public, on the quality of the atmosphere and on ground water. These concerns have prompted many to look for alternative methods by which these products may be formulated. For example, in recent years efforts have been made to reduce the use of chlorofluorohydrocarbons as solvents, propellants, and mold-blowing agents in various products. Also, the EPA has moved to reduce, if not eliminate, the presence of xylene in aromatic-based solvents used in the U.S. Attempts to remedy the problem by substituting another solvent that is environmentally more acceptable have not been satisfactory in that they have failed in most cases to provide the desired economic performance.
Other attempts to solve the problem involve converting the formulation to a physical form which requires no solvent. However, such a change often results in a product of reduced activity. The change in form may also be met with customer resistance or it may generate problems in the physical or chemical stability of the product when it is stored.
In order to insure good economic performance, these formulation systems frequently contain other excipients in addition to the solvent. These excipients may be surface active agents, antimicrobial agents, defoamers, anti-foamers, thickening agents, co-solvents or other chemicals considered important to the producer or end user to insure the economic performance of the active ingredient. Also, these excipients are selected to insure and/or to enhance product performance. This is true regardless of the end use of the product.
Regardless of the role of the excipient in the product, it must, during the formulation process, be brought into intimate contact with the active ingredient as well as the other excipients. In most cases this is accomplished by using the solvent powers of the selected solvent to dissolve the active ingredient. Sometimes this is achieved through the use of cosolvents. Thus, the effort to replace or reduce the use of a solvent will alter how an active ingredient is formulated. In addition, many preparations employ solvents at the same weight percentage as the active ingredient, often the combined weight percentage of excipient plus solvent exceeds that of the active ingredient. Given these levels of excipients in the product, the formulator must also design the product to account for proper performance of the excipients in the expected end use. Furthermore, since solvents often comprise the second largest constituent of a product, second only to the active ingredient on a percentage basis, the performance of the product is also influenced by the solvent. To insure the proper dispersion or emulsification of the oil phase, the chemist selects and adds certain surface active agents to the product to ensure economic performance. Therefore, any changes in the formulation process that eliminate use of solvents or reduce their content has a significant effect on the economic value of the active ingredient as well as the selection of excipients.
It is an object of the invention, therefore, to provide a method of eliminating or greatly reducing the use of harmful solvents in the preparation of formulations useful to the consumer or processor.
Another object of the invention is to provide a method which permits the intimate mixing of active ingredients and excipients on a molecular level usually achieved only when a solvent-based preparation is utilized.
Yet another object of the invention is to provide a solvent-free intimate mix of active ingredient and excipients that maintain the desired activity and stability.
A further object of the invention is to provide a method which produces an environmentally-acceptable final product which does not contain solvents and offers the same or a better level of economic performance as the same product which does contain solvents.
Yet another object is to provide an economical and environmentally-safe method for the production of chemical formulations.
A further object of the invention is to provide a method of formulating intimate mixtures of active ingredients and excipients heretofore impossible or impractical to prepare.